Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response.
Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response.
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DOI：
10.1016/j.redox.2012.10.003
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发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Hill, Bradford G.
中科院分区：
文献类型：
--
作者：
Haberzettl, Petra;Hill, Bradford G.
氧化的脂蛋白和膜脂过度产生不饱和醛是心血管疾病的一个特征。我们以前的研究表明，不饱和脂质过氧化衍生的醛，如4-羟基-反式-2-壬烯醛(HNE)，可促进大鼠主动脉平滑肌细胞(RASMC)的自噬。在这项研究中，我们研究了HNE诱导自噬的机制。RASMC暴露于HNE可引起多种蛋白质的修饰，经质谱仪和共聚焦显微镜鉴定，大部分蛋白质定位于内质网(ER)。HNE刺激PKR样ER激酶和真核细胞起始因子2α的磷酸化，并增加HO-1的丰度。HNE处理也增加了Lc3-II的形成和JNK和p38的磷酸化。药物抑制JNK，而不是p38，可以阻止HNE诱导的HO-1的表达和LC3-II的形成。抑制JNK可增加HNE处理的细胞的死亡。用化学伴侣苯丁酸预处理可阻止LC3-II的形成以及JNK的磷酸化和HO-1的诱导。综上所述，这些数据表明，不饱和醛引发的自噬反应可能部分归因于内质网应激，内质网应激通过JNK依赖的机制刺激自噬，并在氧化应激期间促进细胞存活。►是脂质过氧化产物4-羟基壬烯醛(HNE)，对血管平滑肌细胞内质网(ER)蛋白具有修饰作用。►hne激活自噬。HNE可激活►、PKR样ER激酶(PERK)和应激性激酶JNK.►药理抑制JNK或ER应激可防止血管平滑肌细胞的自噬。
Excessive production of unsaturated aldehydes from oxidized lipoproteins and membrane lipids is a characteristic feature of cardiovascular disease. Our previous studies show that unsaturated lipid peroxidation-derived aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) promote autophagy in rat aortic smooth muscle cells (RASMC). In this study, we examined the mechanism by which HNE induces autophagy. Exposure of RASMC to HNE led to the modification of several proteins, most of which were identified by mass spectrometry and confocal microscopy to be localized to the endoplasmic reticulum (ER). HNE stimulated the phosphorylation of PKR-like ER kinase and eukaryotic initiation factor 2α and increased heme oxygenase-1 (HO-1) abundance. HNE treatment also increased LC3-II formation and the phosphorylation of JNK and p38. Pharmacological inhibition of JNK, but not p38, prevented HNE-induced HO-1 expression and LC3-II formation. Inhibition of JNK increased cell death in HNE-treated cells. Pretreatment with the chemical chaperone phenylbutryic acid prevented LC3-II formation as well as JNK phosphorylation and HO-1 induction. Taken together, these data suggest that autophagic responses triggered by unsaturated aldehydes could be attributed, in part, to ER stress, which stimulates autophagy by a JNK-dependent mechanism and promotes cell survival during oxidative stress. ► The lipid peroxidation product 4-hydroxynonenal (HNE) modifies endoplasmic reticulum (ER) proteins in vascular smooth muscle cells. ► HNE activates autophagy. ► PKR-like ER kinase (PERK) and the stress kinase JNK are activated by HNE. ► Pharmacological inhibition of JNK or ER stress prevents autophagy in vascular smooth muscle cells.
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影响因子：
56.9
作者：
HWANG, C;SINSKEY, AJ;LODISH, HF
通讯作者：
LODISH, HF
影响因子：
2.5
作者：
Butterfield, DA;Reed, T;Sultana, R
通讯作者：
Sultana, R
DOI：
10.1016/0005-2760(82)90292-2
发表时间：
1982-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
BENEDETTI, A;FULCERI, R;COMPORTI, M
通讯作者：
COMPORTI, M
DOI：
10.1042/bj20111752
发表时间：
2012-03-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Higdon A;Diers AR;Oh JY;Landar A;Darley-Usmar VM
通讯作者：
Darley-Usmar VM
影响因子：
3.8
作者：
Haberzettl P;Vladykovskaya E;Srivastava S;Bhatnagar A
通讯作者：
Bhatnagar A